Steve Ealick's Research Group

Human Phosphopantothenoylcysteine Synthetase

PDB file:



Phosphopantothenoylcysteine (PPC) synthetase, which in humans is encoded by the gene coaB, catalyzes the first step in the four-step synthesis of Coenzyme A from phosphopantothenate. The human enzyme has 331 amino acids and requires ATP as a cofactor and produces AMP as one of the products.

The overall fold of the PPP synthetase monomer is an αβα  three-layer sandwich. Each monomer contains a central eight-stranded β-sheet. Three α-helices (α1, α6 and α9) flank one side of the sheet and the remaining four α-helices (α2, α4, α5 and α10) are on the opposite side.

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The active form of PPC synthetase is a homodimer with approximate dimension of 60 Å x 60 Å x 75 Å. The two monomers are related by twofold noncrystallographic symmetr. The monomers form 28 hydrogen bonds between side chains at the interface. In addition, four water molecules bridge amino acid residues between two monomers. A cluster of hydrophobic residues forms in the core of the dimer interface.

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The ATP molecule is located near the ends of strands β1, β6, β7, β8 and b9 and helices α2 and α10. The predicted phosphopantothenate binding site is located in a cleft formed largely by the C-terminal ends of strand β6 and β9. Conserved residues Thr45, Asn59, Ala179 and Ala180 from one monomer and Val54′ and Arg55′ from the adjacent monomer are positioned near the proposed bound phosphopantothenate. Arg55 is positioned to form a hydrogen bond with the phosphate while the carboxylate group is near the α-phosphate of ATP.

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Manoj N, Strauss E, Begley TP and Ealick SE. Structure of Human Phosphopantothenoylcysteine Synthetase at 2.3 Å Resolution. Structure 11: 927-36 (2003).

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